The experimental objective of this proposal is to synthesize a series of 18 squalamine mimics based upon deoxycholic acid, lithocholic acid, and chenodeoxycholic acid ring systems, plus spermine and poly(ethylene glycol)s.These choices are based upon antimicrobial activity observed in a series of 20 compounds which included four of the lead compounds proposed in this application; 2 of the lead compounds have not yet been made.Each of these six lead compounds will be modified to contain 1, 6 or 13 ether units (CH2CH2O) in a polyether chain.The rationale for these experiments is that the repeating ether units add hydrophilicity and increase the critical micellar concentration (cmc), which should lower hemolytic activity of the compounds, if Dr. Regen's hypothesis is correct.Tests to be performed on each sterol conjugate include: determination of the cmc, measurement of membrane rupture versus membrane leakage in 1000 angstrom-diameter unilamellar vesicles; in vitro determination of antimicrobial activityagainst Gram-positive bacteria, Gram-negative bacteria, mycobacteria, and fungi; hemolytic activity against sheep red blood cells; and cytotoxic activity against human H9 cells.The long-term objective of this work is to optimize the therapeutic potential of a new class of antimicrobial sterol conjugates as broadspectrum antibiotics for systemic use.The hypothesis is that monomeric forms of the squalamine mimics will be more selective than the micellar forms because monomeric forms cause a slow leakage of the target membrane whereas micelles cause catastrophic rupture.By making a series of compounds to vary the cmc, this hypothesis can be tested directly.